G-alkyl-z



United States Patent This invention relates to new 6-alkyl-2,4,7-triaminopteridines having pharmacodynamic activity as potent diuretic and antihypertensive agents.

The compounds of this invention are represented more specifically by the structural formula:

in which R is a lower alkyl or a halo-lower-alkyl moiety. Preferably R is lower alkyl of from 1-3 carbons, advantageously methyl.

The compounds of this invention, namely 6-alkyl-7- aminopteridines, cannot be prepared by the methods of the prior art but have unexpectedly been prepared by methods claimed in our earlier copending applications, Serial No. 206,153 filed June 29, 1962 and Serial No. 176,444 filed February 28, 1962, of which this application is a continuation-in-part.

The closest prior art congener is 2,4,7-triaminopteridine disclosed in Osdene et al., J. Chem. Soc., 1955; 2037. The 6-methyl-2,4,7-tria1ninopteridine of this invention has unexpectedly been found very substantially more active than the desmethyl Osdene compound as a diuretic.

Also included in this invention are the nontoxic, pharmaceutically acceptable acid addition salts of the 6-alkyl- 2,4,7-triaminopteridines. These salts are prepared by reacting the base in water or an organic solvent with an excess of the acid as known to the art. Exemplary of such acids are hydrochloric, acetic, phosphoric, sulfuric, ethanedisulfonic, etc., acids.

The preferred method of preparation of the 6-alkyl-7- aminopteridines is by condensing 2,4,5,6-triaminopyrimidine with an aldehyde, RCHO, in the presence of cyanide. Initially a Schitf base is formed to which the elements of HCN are added to form a 5-a-cyanoalky1aminopyrimidine which is cyclized and oxidized to the desired pteridine. The reaction can be carried out with or without isolation of the intermediates. In practice usually only the a-cyanoalkylaminopyrimidine intermediate is isolated.

Alternatively, when the 6-alkyl group has more than a two carbon chain the substituted acrolein may be employed with its a,fi-double bond shifting to form the pteridine ring thereby eliminating the oxidation step. Details of the most preferred processes for preparing these compounds are given in the examples hereafter.

The compounds of this invention have been found to exert diuretic and/ or antihypertensive activity when administered in dosage unit form combined with a pharmaceutical carrier internally, usually orally, to animals.

The term lower alkyl denotes, herein and in the claims, moieties having from 1-6, preferably 13, carbon atoms. The term halo-lower-alkyl denotes lower alkyl moieties substituted by one or more inert halo atom, such as chloro or fluoro.

It will be apparent to one skilled in the art that certain modifications in the basic 6-alkyl-2,4,7-triaminopteridine nucleus can be made without departing from the spirit of this invention, such as N-acylation, N-alkylation or replacement of the primary amine group by standard hetero- 3,127,403 Patented Mar. 31, 1964 cyclic amine groups, such as morpholino, piperidinyl, pyrrolidinyl, etc.

Example 1 A suspension of 9 g. of 2,4,5,6-tetraaminopyrimidine hydrochloride in 50 ml. of methanol and 20 m1. of hydrochloric acid is heated to 50 C. and treated in succession with a solution of 5 g. of sodium cyanide in 20 ml. of water and then with a solution of 3 g. of acetaldehyde in 10 m1. of methanol. After standing for fifteen minutes at room temperature and in the refrigerator for two hours, 2,4,6-triamino-5-(u-cyanoethylamino)-pyrimidine acetate, M.P. 183-184 C., is obtained.

The cyano intermediate (5 g.) is added to a solution of 5 g. of sodium methoxide in ml. of methanol. After heating at reflux for ten minutes, the hot solution is diluted with 80 ml. of water and 10 ml. of 30% hydrogen peroxide. After five hours at room temperature the desired 6- methyl-2,4,7-triaminopteridine, M.P. 340 C., is separated from the reaction mixture by filtration.

This compound is dissolved in hot dilute acetic acid. Cooling separates the acetate salt.

Example 2 Five grams of 2,4,5,6-tetraaminopyrimidine in methanol and acetic acid is heated to 50 C. and treated first with 3.5 g. of sodium cyanide in water and then with 5.8 g. of a,u,a-trifluoroacetaldehyde. Cooling and filtering gives 2,4,6 triamino 5 (woyano-Bfi,fl-trifluoroethylamino)- pyrimidine which on refluxing with sodium ethoxide in ethanol, then cooling, concentrating and refluxing the residue with aqueous hydrogen peroxide gives 2,4,7-triamino- 6-trifluoromethylpteridine.

This compound (500 mg.) is dissolved in hot dilute phosphoric acid. Cooling separates the phosphate salt.

Example 3 NH, in which R is a member selected from the group consisting of halo-lower-alkyl and lower alkyl.

2. 6-methyl-2,4,7-triaminopteridine. 3. 6-trifluoromethyl-2,4,7-triaminopteridine. 4. 6-isopropyl-2,4,7-triaminopteridine. 5. 6-(2-chloroethy1)-2,4,7-triaminopteridine.

References Cited in the file of this patent UNITED STATES PATENTS Roch June 14, 1960 OTHER REFERENCES Wolstenholme et al.: Editors, Chemistry and Biology of Pteridines (Ciba Foundation Symposium) (1954), pages 104 and 116.

Osdene et al.: J. Chem. Soc. London (1955), pages 2036-38. 

1. A CHEMICAL COMPOUND OF THE CLASS CONSISTING OF A FREE BASE AND ITS NONTOXIC, PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS, SAID FREE BASE HAVING THE FORMULA: 